Escape from autologous neutralizing antibodies in acute/early subtype C HIV-1 infection requires multiple pathways.
Escape from autologous neutralizing antibodies in acute/early subtype C HIV-1 infection requires multiple pathways.
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DOI：
10.1371/journal.ppat.1000594
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发表时间：
2009-09
期刊：
影响因子：
6.7
通讯作者：
Derdeyn CA
中科院分区：
文献类型：
--
作者：
Rong R;Li B;Lynch RM;Haaland RE;Murphy MK;Mulenga J;Allen SA;Pinter A;Shaw GM;Hunter E;Robinson JE;Gnanakaran S;Derdeyn CA
HIV疫苗的一个目的是引发中和抗体（Nab），可以限制遗传多样性病毒的复制并防止新感染的建立。因此，在自然感染的早期阶段确定Nab的优势和劣势可能有助于实现这一目标。在这里，我们证明了尽管在两名患有急性/早期C亚型感染的受试者中出现了高滴度自体Nab，但病毒逃逸很容易发生。为了提供逃逸途径的详细描述，在多个时间点鉴定的Nab抗性变体用于在相应的新传播的Env的背景内产生一系列包膜（Env）糖蛋白嵌合体和突变体。在一名受试者中，Nab逃逸主要由从V3结构域开始延伸至V5结构域结束（V3 V5）的gp 120区域的变化驱动。然而，Nab逃逸途径在这个主题振荡，有时需要V1 V2和gp 41胞外域之间的合作。在第二名受试者中，V1 V2的变化驱动了逃逸。这种V1 V2依赖性逃逸途径随着时间的推移而保留，其效用反映在病毒通过在V2中引入单个潜在的N-连接糖基化位点从来自同一患者的两种不同单克隆抗体（Mab）逃逸的能力中。gp 120序列变化的空间表示表明，选择性压力作用于这两个受试者的Env相同区域，即使驱动逃逸的Env结构域不同。总之，研究结果表明，一个单一的突变途径是不足以赋予逃脱早期亚型C HIV-1感染，并支持一种模型，其中多种策略，包括潜在的聚糖移位，直接改变表位序列，和合作的Env结构域构象掩蔽，用于逃避中和。开发艾滋病毒疫苗的一个重大障碍是病毒有可能逃避免疫诱导的免疫反应。我们以前表明，赞比亚队列中的受试者在感染C亚型HIV-1后不久就产生了有效的中和抗体应答，在这里，我们扩展了这些发现，以证明尽管有有效的免疫应答，但其中两名受试者仍发生了病毒逃逸周期。我们研究了免疫逃逸的决定因素，发现单一的共同突变途径不足以促进病毒逃逸。相反，我们证明了多种策略，包括糖基化模式的潜在变化，表位序列的直接改变，以及合作的包膜相互作用，被单独或一起使用，以逃避中和。我们还从其中一名受试者中回收了单个单克隆抗体，发现单个突变可以使其逃避不同的中和抗体特异性。这些研究证明了C亚型HIV-1的显著灵活性，并表明包膜糖蛋白具有独特的能力，可以适应每个新感染宿主的免疫反应的特定特性。
One aim for an HIV vaccine is to elicit neutralizing antibodies (Nab) that can limit replication of genetically diverse viruses and prevent establishment of a new infection. Thus, identifying the strengths and weaknesses of Nab during the early stages of natural infection could prove useful in achieving this goal. Here we demonstrate that viral escape readily occurred despite the development of high titer autologous Nab in two subjects with acute/early subtype C infection. To provide a detailed portrayal of the escape pathways, Nab resistant variants identified at multiple time points were used to create a series of envelope (Env) glycoprotein chimeras and mutants within the background of a corresponding newly transmitted Env. In one subject, Nab escape was driven predominantly by changes in the region of gp120 that extends from the beginning of the V3 domain to the end of the V5 domain (V3V5). However, Nab escape pathways in this subject oscillated and at times required cooperation between V1V2 and the gp41 ectodomain. In the second subject, escape was driven by changes in V1V2. This V1V2-dependent escape pathway was retained over time, and its utility was reflected in the virus's ability to escape from two distinct monoclonal antibodies (Mabs) derived from this same patient via introduction of a single potential N-linked glycosylation site in V2. Spatial representation of the sequence changes in gp120 suggested that selective pressure acted upon the same regions of Env in these two subjects, even though the Env domains that drove escape were different. Together the findings argue that a single mutational pathway is not sufficient to confer escape in early subtype C HIV-1 infection, and support a model in which multiple strategies, including potential glycan shifts, direct alteration of an epitope sequence, and cooperative Env domain conformational masking, are used to evade neutralization. A significant obstacle to developing an HIV vaccine is the potential for the virus to escape from the immune response induced by immunization. We previously showed that subjects in a Zambian cohort developed potent neutralizing antibody responses shortly after becoming infected by subtype C HIV-1, and here we have extended those findings to demonstrate that cycles of viral escape occurred in two of these subjects despite a potent immune response. We investigated the determinants of immune escape, and found that a single common mutational pathway was not sufficient to facilitate viral escape. Instead, we demonstrate that multiple strategies, including potential changes in glycosylation pattern, direct alteration of an epitope sequence, and cooperative envelope interactions, were used independently or together to evade neutralization. We also recovered individual monoclonal antibodies from one of the subjects and found that a single mutation can confer escape from different neutralizing antibody specificities. The studies demonstrate the remarkable flexibility of subtype C HIV-1, and suggest that the envelope glycoproteins are uniquely equipped to adjust to the specific properties of the immune response in each newly infected host.
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